1. Field of the Invention
The present invention relates to the use of Coenzyme Q10 (or ubiquinone Q10 or quinone Q10, CoQ10) or functionally equivalent derivatives thereof, for the prevention, the treatment and/or attenuation of degenerative ocular pathologies of a heredofamilial, inflammatory, dysmetabolic, senile age-related nature, the degenerative process deriving from apoptotic phenomena i.e. programmed cell death (PCD).
The present invention also envisages the systemic or topical administration of the Coenzyme Q10 or functionally equivalent derivatives thereof.
2. Description of the Prior Art
Apoptosis, or programmed cell death (PCD), is involved in a large quantity of degenerative pathologies including pathologies of the eye's posterior chamber and of the perioptic area. Among these diseases there are heredofamilial, inflammatory, dysmetabolic and age-related macular and retinal degenerations e.g.: the glaucoma, the age-related macular degeneration, the retinitis pigmentosa, various heredofamilial maculopathies such as the Stargardt disease, the vitelliform macular cysts and the cones dystrophy, the diabetic retinopathy (exudative or proliferating), the hypertensive retinopathy, the ischemic opticopathy, the senile opacity of lenses, the cataract, the detachment of the retina, the uveitis, the retinoblastoma, the neuritis and the optical neuropathies of toxic, inflammatory and degenerative origin.
In all these pathologies the degeneration is due to the cell death through apoptosis.
The glaucoma may be taken as a paradigmatic example of such group of pathologies, in which apoptotic events play a major role, both for the pathogenetic mechanisms involved and for the spread of said disease. The glaucoma is an optical neuropathy, which determines a loss of ganglion cells, with a progressive loss of the visual field and of the visual function and subsequent excavation of the optic nerve head. The high intraocular pressure is a risk factor for the development of the disease and it is known that the decrease of the intraocular pressure protects the optic nerve from further damages.
In patients affected by glaucoma, the course of the disease is, usually, slow and irregular, with a marked interindividual variability. Although it does not seem that there is a direct correlation between the ganglion cells death and the progression of the visual field defects, it is believed that the cells loss precedes the onset of the visual field alterations. The progressive loss of the visual function was associated with several risk factors, such as the high intraocular pressure or the presence of a local or systemic deregulation of the haematic flow. Since experimental and clinic tests have demonstrated that ocular hypertension is a causal factor for the growth of the glaucomatous optical neuropathy, the universally accepted treatment is, at present, essentially limited to the reduction of the intraocular pressure, e.g., through medicaments having a diuretic effect, β-blocking medicaments, and others.
Said observations do not only concern human beings, but also mammals in general and, more particularly, house pets.
Recently, in vitro and in vivo studies on animal models, have suggested the possibility that a patient affected by glaucoma could benefit from a neuroprotective treatment, aimed at slowing down the progression of the death of ganglion cells (Nickells R. W. Apoptosis of retinal ganglion cells in glaucoma: an update of the molecular pathways involved in cell death. Surv Ophtalmol 1999; 43: S151–161). Furthermore, it is known that the highest part of retinal ganglion cells in glaucoma die through apoptosis (Kerrigan L. A., Zack D. J., Quigley H. A., et al. TUNEL-positive ganglion cells in human primary open-angle glaucoma. Arch Ophtalmol 1997; 115: 1031–1035) and that the hypoxia subsequent to ischemia is one of the ascertained causes of said cellular death (Gross R. L., Hensley S. H., Gao F., Wu S. M. Retinal ganglion cell dysfunction induced by hypoxia and glutamate: potential neuroprotective effects of beta-blockers. Surv Ophtalmol 1999, 43 Suppl:S162–70).
Although glaucoma has been herein used as a paradigmatic example, all the above mentioned degenerative pathologies share two common features, they damage the posterior part of the eye (i.e. retina and/or optic nerve) and they undergo several kind of apoptotic events in said tissues, said apoptotic events being caused by very different phenomena such as: ischemia, hypoxia/anoxia, lack of trophic factors, presence of free radicals.
Taking into account the common features shared by the above-mentioned pathologies, there is the need of providing means for the treatment, attenuation or prevention of all the above mentioned apoptotic events, hence, aiming at a neuroprotective activity in the posterior part of the eye.
PCT WO01/37851, in the name of the same Applicant of the present application, discloses the use of Coenzyme Q10 in the prevention of PCD deriving from corneal photo refractive surgery treatments (anterior part of the eye) by means of excimer laser and exposure to ultraviolet rays.
The above-mentioned patent application teaches how to contend corneal cell apoptosis (anterior part of the eye) triggered by the creation of free radicals produced by electromagnetic radiations.
Coenzyme Q10, or ubiquinone, is a coenzyme present in the cell on the mitochondrial internal membrane where its function, in association with a series of factors, in the electrons transport chain, which culminates with the production of energy in the form of adenosine triphosphate (ATP), is crucial. Moreover, Coenzyme Q10 is an active scavenger of free radicals and its presence, associated exactly with said activity, has been detected also at the plasma membrane level. It has to be pointed out that the actual therapies of, e.g. glaucoma, are essentially limited to the reduction of the intraocular pressure and do not envisage a neuroprotective activity. To date, on the contrary, there is no knowledge concerning the activity of Coenzyme Q10 as a molecule that could have anti-apoptotic properties in pathological conditions wherein the apoptotic event can be also independent from the increase of free radicals. This is, in particular, the case of apoptosis due to ischemia, hypoxia/anoxia, lack of trophic factors. There is namely no news about the fact that Coenzyme Q10 can function also in a different way with respect to its well-known antioxidant action. There is, therefore, the need for a neuroprotective therapy for the degenerative diseases of the posterior part of the eye, aimed at impeding, slowing or preventing the programmed cell death independently from the mechanisms entailing said PCD.
Said need derives from the observation that, among pathologies of the eye such as heredofamilial, inflammatory, dysmetabolic and age-related macular and retinal degenerations, the degenerative process due to apoptosis is not uniformly caused but is caused by an admixture of apoptotic phenomena triggered by different stimuli such as free radicals excess, ischemia, hypoxia/anoxia, lack of trophic factors. In all said pathologies the majority of the apoptotic events is not attributable to the presence of free radicals.